Definition: A benign smooth muscle tumor of the myocardium, consisting of immature myocytes.

Prevalence: Tuberous sclerosis: 0.2-1:10,000 persons1,2; rhabdomyoma in association with tuberous sclerosis: up to 50-60% of cases3-5.

Etiology: Tuberous sclerosis is an autosomal dominant Mendelian condition, though the majority of new cases represent new mutations. At least two gene loci have been identified (chromosomes 9 and 11) 6-8. The cause for associated tumor generation is unknown.

Pathogenesis: Rhabdomyomas are probably not true neoplasms, but rather hamartomas, with few mitotic figures and the absence of metastases.

Tuberous sclerosis is a genetic disease with protean manifestations which affect almost all organ systems. The condition is passed in an autosomal dominant manner, though there are many cases of new mutations20. Definitive antenatal diagnosis using DNA probes or linked markers has not yet been achieved. However, myocardial rhabdomyomata are among the classic manifestations of the disease and, not uncommonly, are discovered in the neonatal period. Prenatal diagnosis may be made with appropriate family history and visualization of characteristic tumors on ultrasonographic examination21-32. We present a kindred with tuberous sclerosis, describe two fetuses in this family with cardiac tumors, and examine their postnatal course.

Case #1

An 18-year-old G1P0 with known tuberous sclerosis presented at 35 weeks of gestation with polyhydramnios. A brother and nephew also had tuberous sclerosis. Fetal echocardiography revealed a 60x45x60 mm echodense mass attached to the left ventricle and cardiac apex (fig. 1).

Figure 1: Left longitudinal view of fetal heart in case #1. A large echodense mass, outlined by a pleural effusion (PE), fills the large chest. The stomach (ST) is noted just below the diaphragm.

A smaller tumor mass was associated with the right ventricular wall (fig. 2).

Figure 2: Four-chamber view of fetal heart in case #1 (only the right atrium [RA] and right ventricle [RV] are labelled). A mass attached to the right ventricular wall and bulging into a pleural effusion (PE) is imaged.

A significant pericardial effusion was noted. A cordocentesis demonstrated a normal female karyotype. At 37 weeks" gestation, an amniocentesis confirmed pulmonary maturity. A primary cesarean section was performed so that the appropriate neonatal support personnel could be present. Birth weight was 2,936g. Intubation was required because of a decreased oxygen saturation and carbon dioxide retention. An aortogram and serial echocardiography confirmed the presence of inoperable rhabdomyomas, mitral and tricuspid regurgitation, a patent ductus arteriosus which closed with Indomethacin therapy, and a pericardial effusion which resolved after a single pericardiocentesis. Extubation was accomplished, feedings began, and there was no evidence of congestive heart failure when the infant was discharged. Tumor size remained unchanged on subsequent echocardiographic examinations, and there never was any evidence of outflow tract obstruction or hemodynamic compromise. Surgical resection was not believed to be an option. The child is now 2 years old, and remains asymptomatic despite persistance of the cardiac tumors. The facial features of the mother are shown in fig. 3.

About 4 months after the patient in case #1 presented, her brother"s spouse, a G2P1, was found to be carrying a fetus with two cardiac tumors. This patient"s previous child had tuberous sclerosis but no associated cardiac lesions. The brother had known tuberous sclerosis (see pedigree in fig. 4).

Fetal ultrasonographic study demonstrated an echodense mass filling the left ventricle. A smaller tumor near the right ventricular outflow tract was noted. An elective repeat cesarean section was performed at 38 weeks" gestation after an amniocentesis demonstrated pulmonary maturity. Birth weight was 3,799g. The infant required nasal continuous positive airway pressure and was rapidly weaned to room air. Postnatal echocardiography confirmed the presence of two cardiac tumors consistent with rhabdomyomas, and an MRI of the brain revealed parenchymal hamartomatous lesions. The infant was discharged without evidence of cardiac decompensation. However, the infant died suddenly at the age of 2 months, presumably from the onset of an arrhythmia.

Discussion

Prevalence

Cardiac tumors are rare, with an incidence among patients of all ages of about 1 in 10,00033. In the neonate, the rhabdomyoma is the most common tumor, accounting for up to 60% of such lesions34. There have been at least 13 reports of antenatal diagnosis, associated with tuberous sclerosis (reviewed in table I). Since as many as 50% of pediatric patients with tuberous sclerosis will present with rhabdomyomas35,36, these tumors can serve as markers for this disease, especially in families previously identified as genetic carriers. Crawford et al21 were the first to suggest that rhabdomyomas can identify tuberous sclerosis on an antenatal basis. Subsequently, other investigators have confirmed that the prenatal diagnosis of a rhabdomyoma is preliminary evidence that the fetus will have other postnatal manifestations of tuberous sclerosis. Unfortunately, many cases of tuberous sclerosis are new mutations, and a familial history of the disease is often negative.

Etiology

Recent studies have delineated at least two genetic loci, on the long arm of chromosome 9 (9q34) and the long arm of chromosome 11 (11q23)6-8. Additional loci are possible and are being actively investigated. The specific gene deficit itself is unknown, as is the underlying process by which the tumor is produced.

A cardiac rhabdomyoma associated with tuberous sclerosis is considered a benign hamartoma of muscle cells. It does not appear to represent a true neoplasm14, with unchecked cellular mitoses and metastases.

Prenatal diagnosis

Table 1 reviews those case reports which have detected cardiac rhabdomyomas in the prenatal period, in association with tuberous sclerosis. Only reports of such tumors in association with tuberous sclerosis have been included. The tumors are often multiple and present as echodense masses in the myocardium. Tumor size is variable, with some tumors being only a few millimeters in diameter. The largest rhabdomyoma noted in the prenatal literature is presented in our case report. Though the cardiac tumors may be correlated with fetal hydrops or arrhythmias, the massive tumor in this case did not appear to compromise the fetus. A careful search for extracardiac hamartomas should be performed in all cases of fetal cardiac tumors, since such lesions are common in tuberous sclerosis. The extracardiac tumors typically found in children and adults with tuberous sclerosis have thus far not been described in association with cardiac rhabdomyomas on prenatal ultrasound examinations. It is clear that a family history of tuberous sclerosis should mandate the search for cardiac lesions in the fetus of carrier parents. Similarly, any fetus discovered to have a cardiac tumor on ultrasonographic study should require a careful pedigree analysis for tuberous sclerosis in other family members.

Differential diagnosis

The differential diagnosis of any cardiac tumor discovered in the antenatal period should include a teratoma, sarcoma, myxoma, and fibroma (p 2127-5)5.

Prognosis and management

Most fetuses with rhabdomyomas in association with tuberous sclerosis do well in the antenatal period. Occasionally, arrhythmias may be noted on fetal heart rate monitoring10, and in at least one report a rhabdomyoma was related with fetal hydrops13. After birth, the natural history of cardiac rhabdomyomas remains uncertain. Some patient series have suggested a poor outcome with a high mortality rate14,37-39. More recently, some reports have noted the spontaneous regression of these tumors15,16,18,19,40,41. In earlier reports, the worse prognosis may reflect autopsy data rather than cases diagnosed early and followed prospectively using ultrasonographic or other techniques. The reports of spontaneous tumor regression may be consistent with the hamartomatous nature of these lesions.

In the fetus with a rhabdomyoma, serial ultrasound evaluation is indicated to rule out the onset of fetal cardiac decompensation and hydrops. A careful family history may reveal tuberous sclerosis, if this disease is not already obvious in the index case. Tuberous sclerosis in a parent may present with facial angiofibromas Fig. X and hypopigmented skin lesions, and a history of convulsions or mental deficits. Appropriate genetic counselling should be offered to the parturient and other family members. The absence of a family history of the disease does not rule out tuberous sclerosis in the fetus, as many cases may represent new mutations2. After delivery, if the neonate is not presenting with significant hemodynamic compromise, expectant observation for tumor regression should be considered. Serial ultrasound evaluation, magnetic resonance imaging, and, in some cases, angiography may be indicated. Surgery may not be necessary, even with massive tumor sizes, especially if tumor regression can be documented. When cardiac outflow obstruction, persistent arrhythmias, cardiac failure, or cardiogenic emboli are present, surgical resection could be lifesaving17-19. However, surgery may not be possible because of tumor size or position. Delivery at a tertiary care center, with pediatric cardiology and surgery services, is recommended.